EP2645994B1 - Formulierungen enthaltend methylthioninium chlorid - Google Patents

Formulierungen enthaltend methylthioninium chlorid Download PDF

Info

Publication number
EP2645994B1
EP2645994B1 EP11802119.5A EP11802119A EP2645994B1 EP 2645994 B1 EP2645994 B1 EP 2645994B1 EP 11802119 A EP11802119 A EP 11802119A EP 2645994 B1 EP2645994 B1 EP 2645994B1
Authority
EP
European Patent Office
Prior art keywords
mtc
composition
diluent
tablets
tablet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP11802119.5A
Other languages
English (en)
French (fr)
Other versions
EP2645994A2 (de
Inventor
Karrar Ahmad Khan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wista Laboratories Ltd
Original Assignee
Wista Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wista Laboratories Ltd filed Critical Wista Laboratories Ltd
Publication of EP2645994A2 publication Critical patent/EP2645994A2/de
Application granted granted Critical
Publication of EP2645994B1 publication Critical patent/EP2645994B1/de
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to solid dosage forms of methylthioninium chloride and to methods of preparing such solid dosage forms.
  • the invention relates to tablet formulations in which the polymorphic form of the active ingredient is stable.
  • Methylthioninium chloride [3,7-bisdimethylaminophenazothionium chloride, C 16 H 18 ClN 3 S, 319.85 g/mol], commonly known as methylene blue, was prepared for the first time in 1876 ( The Merck Index, 13th edition, Merck & Co., Inc., 2001, entry 6085 ).
  • MTC Methylthioninium chloride
  • WO 2006/032879 also discloses a number of applications of methylene blue, which include use as a medical dye, as a redox indicator, as an antiseptic, for the treatment and prevention of kidney stones, and for the treatment of melanoma, malaria, and viral infections.
  • MTC has also been used as an oxidizing agent and as an antidote in the case of carbon monoxide, nitrite and aniline poisoning.
  • PhosphasalTM for oral administration (see www.drugs.com/pro/phosphasal.html; PhosphasalTM is a trademark of Stellar Pharmacal).
  • PhosphasalTM is a trademark of Stellar Pharmacal.
  • Each tablet is reported to contain Methenamine, 81.6 mg, Sodium Phosphate Monobasic, 40.8 mg, Phenyl Salicylate, 36.2 mg, Methylene Blue, 10.8 mg, and Hyoscyamine Sulfate, 0.12 mg as well as inactive ingredients: Crospovidone, Dicalcium Phosphate, FD&C Blue #1 Aluminum Lake, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinyl Alcohol, Stearic Acid, Talc, and Titanium Dioxide. The drug is apparently not approved for any specific indication, but the methylene blue ingredient is reported to possess weak antiseptic properties.
  • MTC has also been proposed for treatment of mild to moderate dementia of the Alzheimer's type (DAT), also known as Alzheimer's disease (AD), a severe irreversible neurodegenerative disease resulting in complete loss of mental faculties.
  • DAT Alzheimer's type
  • AD Alzheimer's disease
  • WO96/30766 describes the use of tau aggregation inhibitors - including MTC for the treatment of various diseases of protein aggregation including AD.
  • Other disclosures of phenothiazines in the area of neurodegenerative disorders include WO 02/075318 , WO 2005/030676 , WO 02/055720 , WO2007110627 , WO2009/060191 , WO2009/044127 .
  • MTC in common with many solid substances useful as active pharmaceutical ingredients, exhibits polymorphism, i.e. it exists in more than one physical form, known as polymorphs, which are typically different crystalline and hydrate forms of the drug substance. Hydrates are crystalline solids containing differing amounts of water incorporated into the crystal structure.
  • MTC Fluka catalogue states in very general terms that MTC may contain up to 22% water (Fluka Catalogue 1997/1998, Fluka Chemie AG, 1997]. MTC is generally considered to exist as a trihydrate, but this was disputed as long as 80 years ago, and non-specific adsorption of water by MTC was proposed instead ( H. Wales, O.A. Nelson, J. Am. Chem. Soc. 45 (1923) 1657 ). A pentahydrate including single crystal X-ray data was described later by several authors ( J.O. Warwicker, J. Chem. Soc. (1955) 2531 and H.E. Marr III, J.M. Stewart, M.F. Chiu, Acta Cryst. B29 (1973) 847 ).
  • This pentahydrate consists of ⁇ -stacked columns of MTC molecules arranged in planes perpendicular to the ⁇ -axis of the crystal.
  • the water molecules and chloride ions are located between these layers, whereas the chloride ions are concentrated in planes almost perpendicular to the water planes and parallel to the axis of the columns.
  • the chloride ions are coordinated with three hydrogen bonds from 3/2 water molecules. Presumably, the same structure was earlier attributed to a tetrahydrate ( W.H. Taylor, Z. Krist. 91 (1935) 450 ).
  • Form A has been identified as a pentahydrate and "Form B” as a dihydrate.
  • Form A is considered stable at high relative humidity (RH) down to approximately 35% RH.
  • RH relative humidity
  • Form A is even observed down to RH less than 20%.
  • Forms C, D and E Several other polymorphs of MTC, referred to as Forms C, D and E, have also been identified. It has been found that the dihydrates B and D are metastable forms over the whole range of water activity and are only kinetically favoured under certain preparation conditions. Form B seems to be the product of incomplete drying of Form A. Form D was obtained in precipitation experiments. No anhydrate form has been identified, but X-ray diffractograms include peaks that cannot be attributed to any of the five known forms. It is therefore likely that the polymorphism of MTC is even more complex than has hitherto been established.
  • polymorphic forms of a drug molecule may have different chemical and/or physical properties.
  • polymorphs can differ substantially in melting point, chemical reactivity, particle size, shape, flow characteristics, caking, degree of hydration or solvation, optical and electrical properties vapour pressure, and density.
  • certain polymorphs of a drug molecule can be more stable than others under given environmental conditions.
  • MTC has a number of properties which render its formulation into a dosage form quite difficult.
  • the distinct blue colour presents processing and cleaning challenges.
  • the existence of numerous polymorphic forms is problematic.
  • the physical stability of the polymorphic Form A is problematic, as during heating and/or storage it can be converted into the polymorphic Forms B and D.
  • the interconversion of the individual crystalline polymorphic forms of MTC in a medicament, during manufacture and/or storage is undesirable as it is a general regulatory requirement that the identity of the medicament must be guaranteed throughout its entire shelf life.
  • the limited stability domain of all MTC polymorphic forms requires an innovative approach to formulation to produce a consistent dosage form.
  • the product quality should be consistent and reproducible at the time of manufacture and on storage at temperatures and relative humidity levels typically encountered in most countries of the world.
  • One may additionally seek other desirable properties in a formulation such as fast dissolution so that the tablet quickly dissolves and the medicine is available for absorption, and also properties such as good compressibility and robustness, and ease of manufacture. Accordingly, good storage stability and fast dissolution are important and desirable attributes for immediate release tablet formulations and capsules.
  • Processes used for tablet formulation and film coating often require the use of heat accompanied by low humidity during the drying process.
  • a material such as MTC, with complex polymorphism, such processes can lead to changes in the physical form of the active ingredient, and hence potentially to instability in the performance of the product.
  • the most commonly used method for the preparation of solid dosage forms is wet granulation. This involves adding a granulating fluid to a powder.
  • the granulating fluid may be water or some other solvent that is sufficiently volatile that it can subsequently be removed by drying.
  • the granulating fluid may also include a binder. Once the solvent has been removed, the resulting mass is milled.
  • wet granulation is often preferred over direct compression because wet granulation is more likely to overcome any problems associated with the physical characteristics of various ingredients in the formulation.
  • Wet granulation provides material which has the required flow and cohesive properties necessary to obtain an acceptable solid dosage form.
  • the content uniformity of the solid dosage form is generally improved with wet granulation because all of the granules usually contain the same amount of drug. Segregation of the drug from excipients is also avoided.
  • the present invention provides novel formulations (tablets and capsules), particularly immediate release formulations, of MTC having one or more desirable properties such as those described above e.g. a consistent and reproducible composition at the time of manufacture, stability on storage at temperatures and relative humidity levels typically encountered in most countries of the world, fast dissolution, robustness, and ease of manufacture.
  • tablet dosage forms and processes for the production thereof provided by direct compression (e.g. simple direct compression), dry granulation, or moist granulation of excipients, followed by drying and addition of the active ingredient extra-granularly.
  • direct compression e.g. simple direct compression
  • dry granulation e.g. dry granulation
  • moist granulation e.g. moist granulation of excipients
  • drying and addition of the active ingredient extra-granularly e.g. simple direct compression
  • such processes can avoid the application of heat or excessive moisture to the MTC, but nevertheless produce a formulation having one or more of the desirable properties above.
  • MTC notably MTC of polymorphic Form A but also other Forms or mixtures of Forms, such as a mixture of Forms B and C
  • MTC has also been found to be stable in a directly compressed solid dosage form such as a tablet, during manufacture and storage, and is not converted into another polymorphic form (in particular Form A is not converted to the Forms B, C or D).
  • MTC when processed by conventional granulation processes, in which, for instance, MTC of Form A can be converted to a substantial extent into Forms B, C and/or D.
  • a pharmaceutical composition in solid dosage form comprising, as active ingredient, MTC, said composition further comprising at least one diluent suitable for direct compression which is microcrystalline cellulose or a sugar, wherein the MTC exists in a substantially pure and stable polymorphic form, which is polymorph Form A wherein the amount of MTC in the composition is more than 10% w/w, and wherein the composition is obtained by a process comprising the dry compression of an intimate powder mixture of the MTC in a substantially pure polymorphic form with the at least one diluent suitable for direct compression, and optionally one or more other excipients.
  • a process for the manufacture of a pharmaceutical composition according to the first aspect comprises the direct compression of an intimate powder mixture of MTC in a substantially pure polymorphic form, which is polymorph Form A, with at least one diluent suitable for direct compression, and optionally one or more other excipients.
  • a free-flowing, cohesive powder comprising MTC in a substantially pure polymorphic form, at least one diluent suitable for direct compression, and optionally one or more other excipients, said powder being capable of being directly compressed into a pharmaceutical composition according to the first aspect.
  • the invention provides pharmaceutical compositions comprising MTC in solid dosage form, the composition further comprising at least one diluent suitable for other dry compression methods e.g. based on dry granulation, or moist granulation of excipients, followed by drying and addition of the active ingredient extra-granularly.
  • diluent suitable for other dry compression methods e.g. based on dry granulation, or moist granulation of excipients, followed by drying and addition of the active ingredient extra-granularly.
  • 'Dry compression' refers to compression techniques which do not involve the use of excessive heat or moisture in respect of the active ingredient (here: MTC).
  • the free-flowing, cohesive powder comprising a compound of the invention (here: MTC) and at least one diluent suitable for dry granulation and optionally one or more other excipients (particularly a lubricant) can be used in methods such as "slugging" or those using a "roller compactor". Such processes form further embodiments of the invention as defined in the claims.
  • the dry granulation is carried out by blending MTC. optionally with a lubricant, with wet-massed excipients, which are dried before the blending step.
  • Solid dosage forms according to the invention exhibit long term chemical and crystallographic stability of the active ingredient, MTC.
  • the pharmaceutical compositions according to the invention have very good dissolution rates even after long term storage.
  • a "substantially pure" polymorphic form of MTC is one in which the predominant polymorphic form of MTC accounts for at least 80% w/w of the material, or at least 90% w/w, or at least 95% w/w. In other words, the material contains less than 20% w/w, or less than 10% w/w or less than 5% w/w of polymorphic forms other than the predominant form.
  • a "substantially pure and stable polymorphic form" of MTC is one in which the predominant polymorphic form remains substantially pure in the composition even after prolonged storage under controlled conditions of temperature and humidity.
  • the MTC in the solid dosage form will substantially maintain its polymorphic identity when stored under chosen environmental conditions.
  • the predominant polymorphic form of the MTC in the composition will exhibit less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 % conversion to polymorphic forms other than the predominant form when stored under controlled conditions for a defined period of time.
  • Preferred controlled conditions are storage in a blister pack (preferably one having aluminum cavity and aluminum foil) which is thus substantially moisture-impervious.
  • the controlled temperature is 25°C and the controlled storage humidity is 65% RH.
  • the defined period of time is 9 months.
  • preferred embodiments of the invention may demonstrate stability even at higher temperatures or different humidities (e.g. 30 or 40°C / 75% RH) and longer periods e.g. 10.5 months, 12 months, 24 months, or 36 months.
  • the conversion between polymorphic forms may conveniently be assessed by X-ray powder diffractograms.
  • the blister pack is opened and the tablet cores are slightly crushed in order to obtain a suitable powder that can be prepared on an XRPD sample holder.
  • the different polymorphs show characteristic signals in the 2q range below 12°, which will be essentially free of signals from the excipients.
  • An evaluation of the XRPD signals in this 2q range permits an unambiguous assignment of the solid state polymorphic forms of MTC in the sample.
  • the absence of any signals from lower hydrates may be verified (here the absence of a signal would typically be defined by a signal intensity which does not exceed three times the noise).
  • Initial assessment may be followed by quantification of each polymorph (if present) by use of appropriate reference measurements of mixtures of different polymorphs.
  • Also described herein is a system comprising a diluent and direct compression (or dry granulation) for enhancing the stability of a substantially pure MTC polymorph in a pharmaceutical composition.
  • the MTC is used in polymorph Form A.
  • use of the present invention minimises conversion of Form A to the Forms B, C or D.
  • the amount of MTC in the uncoated composition is more than about 10% w/w, but can be more than 20%, or more than 30% w/w.
  • the amount of MTC is generally less than about 70% w/w, and usually less than 60% or less than 50% w/w.
  • the amount of MTC in the uncoated composition is thus from about 10% w/w (or 20% or 30%) to about 70% w/w (or 60% or 50%).
  • MTC is not inherently compressible and thus requires addition of suitable diluents to aid compression.
  • compositions of the invention therefore commonly comprise at least 15% w/w, more commonly at least 20%, at least 30%, at least 40% or at least 50% w/w of diluent(s).
  • Diluents that may be used include one or more of microcrystalline cellulose and sugars such as lactose, sucrose, dextrose and maltodextrin.
  • Preferred diluents are microcrystalline cellulose, lactose and mannitol. Spray-dried forms of lactose and mannitol are particularly suitable forms of those compounds.
  • MTC of a particular polymorphic form here: Form A
  • direct compression diluents such as one or more of microcrystalline cellulose, spray dried lactose, anhydrous lactose and mannitol
  • the resulting solid dosage forms are stable in the sense that the polymorphic form of the MTC is preserved, and the MTC remains chemically stable, even after extended storage.
  • the invention thus provides a method of preparing low-, medium- or high-dose MTC tablets that are stable and have acceptable dissolution profiles, acceptable degrees of hardness and resistance to chipping, as well as a short disintegration time.
  • the pharmaceutical composition will generally also include a lubricant.
  • lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glycerylbehaptate, polyethylene glycol, ethylene oxide polymers (for example, those available under the registered trademark Carbowax from Union Carbide, Inc., Danbury, CT), sodium lauryl sulphate, magnesium lauryl stearate, mixtures of magnesium stearate with sodium lauryl sulphate, and hydrogenated vegetable oil.
  • Preferred lubricants include calcium stearate, magnesium stearate and sodium stearyl fumarate. Most preferred as the lubricant is magnesium stearate.
  • Lubricants generally comprise from about 0.5 to about 5.0% of the total (uncoated) tablet weight. The amount of lubricant employed is generally from about 1.0 to about 2.0%, preferably 0.5 to 2.0% w/w.
  • excipients may also be present in the pharmaceutical compositions of the invention.
  • additional excipients include disintegrants, binders, flavouring agents, colours and glidants.
  • Some excipients can serve multiple functions, for example as both binder and tablet disintegrant.
  • a tablet disintegrant may be present in an amount necessary to achieve rapid dissolution.
  • Disintegrants are excipients which oppose the physical forces of particle bonding in a tablet or capsule when the dosage form is placed in an aqueous environment.
  • examples of disintegrants include crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked sodium carboxymethyl cellulose (sodium croscarmellose), and pregelatinized starch.
  • the amount of disintegrant can be from 0 to about 25% w/w, more commonly from about 1% to about 15% w/w, and usually less than 10% or less than 5% w/w, of the composition.
  • Binders are excipients which contribute to particle adhesion in a solid formulation.
  • binders include cellulose derivatives (carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, ethylcellulose, microcrystalline cellulose) and sugars such as lactose, sucrose, dextrose, glucose, maltodextrin, and mannitol, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, pregelatinized starch, alginic acids, and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, and the like.
  • the amount of binder can vary widely, e.g. from 0% to 95% w/w of the composition.
  • excipients may serve multiple functions.
  • the tabletting diluent may also serve as a binder.
  • Glidants are substances added to a powder to improve its flowability.
  • examples of glidants include magnesium stearate, colloidal silicon dioxide (such as the grades sold as Aerosil), starch and talc.
  • Glidants may be present in the pharmaceutical composition at a level of from 0 to about 5% w/w. Again, however, it should be noted that excipients may serve multiple functions.
  • the lubricant for example magnesium stearate, may also function as a glidant.
  • colours examples include titanium dioxide and/or dyes suitable for food such as those known as FD&C dyes and natural colouring agents.
  • a colouring agent is unlikely to be used in the powder mixture that is compressed in accordance with the second aspect of the invention, but may form part of a coating applied to the composition, as described below, in which case the colouring agent may be present in the film coat in an amount up to about 2.0% w/w.
  • composition is a tablet
  • this is desirably coated with a conventional film coating which imparts toughness, ease of swallowing, and an elegant appearance to the final product.
  • Many polymeric film-coating materials are known in the art.
  • a preferred film-coating material is hydroxypropylmethylcellulose (HPMC) or polyvinyl alcohol-part hydrolysed (PVA).
  • HPMC and PVA may be obtained commercially, for example from Colorcon, in coating formulations containing excipients which serve as coating aids, under the registered trademark Opadry.
  • Opadry formulations may contain talc, polydextrose, triacetin, polyethyleneglycol, polysorbate 80, titanium dioxide, and one or more dyes or lakes.
  • film-forming polymers may also be used, including hydroxypropylcellulose, vinyl copolymers such as polyvinyl pyrollidone and polyvinyl acetate, and acrylate-methacrylate copolymers.
  • Use of a film coating is beneficial for ease of handling and because a blue coloured uncoated core may stain the inside of the mouth during swallowing. Coating also improves light stability of the dosage form.
  • Coating of the tablets may conveniently be carried out using a conventional coating pan.
  • the coating pan is pre-heated using heated inlet air until the exhaust temperature reaches 35-55°C, more preferably 40-50°C. This may typically require application of heated inlet air at an inlet temperature of 45-75°C, preferably 50-65°C, for 10-15 minutes.
  • the MTC tablets are then added to the coating pan and the aqueous film coat applied.
  • the spray rate is controlled such that the bed temperature is maintained at 38-48°C, more preferably 42-44°C, until the desired weight gain (coating weight) has been achieved.
  • Described herein is a method of treatment or prophylaxis of a disease condition in a patient, comprising administering to said patient a therapeutically-effective amount of a solid dosage form composition as described herein.
  • Described herein is a method of treatment or prophylaxis of a tauopathy condition in a patient, comprising administering to said patient a therapeutically-effective amount of a solid dosage form composition as described herein.
  • prophylaxis in the context of the present specification should not be understood to circumscribe complete success i.e. complete protection or complete prevention. Rather prophylaxis in the present context refers to a measure which is administered in advance of detection of a symptomatic condition with the aim preserving health by helping to delay, mitigate or avoid that particular condition.
  • tauopathies As well as Alzheimer's disease (AD), the pathogenesis of neurodegenerative disorders such as Pick's disease and Progressive Supranuclear Palsy (PSP) appears to correlate with an accumulation of pathological truncated tau aggregates in the dentate gyrus and stellate pyramidal cells of the neocortex, respectively.
  • Other dementias include fronto-temporal dementia (FTD); FTD with parkinsonism linked to chromosome 17 (FTDP-17); behavioural variant FTD (bvFTD); progressive nonfluent aphasia (PNFA) Josephs, KA, Petersen, RC, Knopman, DS, et al.
  • FTD fronto-temporal dementia
  • FTDP-17 FTD with parkinsonism linked to chromosome 17
  • bvFTD behavioural variant FTD
  • PNFA progressive nonfluent aphasia
  • Senile dementia of Lewy body type and Alzheimer type are biochemically distinct in terms of paired helical filaments and hyperphosphorylated tau protein. Dementia 5, 215-228 ).
  • Tau-positive NFTs are also found in Postencephalitic parkinsonism (PEP) ( Hof P.R., Charpiot, A., Delacourte A., Buee, L., Purohit, D., Perl D.P. and Bouras, C. (1992) Distribution of neurofibrillary tangles and senile plaques in the cerebral cortex in postencephalitic parkinsonism. Neurosci. Lett. 139, 10-14 ).
  • Glial tau tangles are observed in Subacute sclerosing panencephalitis (SSPE) ( Ikeda K., Akiyama H., Kondo H., Arai T., Arai N. and Yagishita S. (1995) Numerous glial fibrillary tangles in oligodendroglia in cases of subacute sclerosing panencephalitis with neurofibrillary tangles. Neurosci. Lett., 194, 133-135 ).
  • SSPE Subacute sclerosing panencephalitis
  • tauopathies include Niemann-Pick disease type C (NPC) ( Love, S., Bridges, L.R. & Case, C.P. (1995), Brain, 118, 119-129 ); Sanfilippo syndrome type B (or mucopolysaccharidosis III B, MPS III B) ( Ohmi, K., Kudo, L.C., Ryazantsev, S., et al. (2009) PNAS, 106, 8332-8337 ; myotonic dystrophies (DM), DM1 ( Sergeant, N., Sablonniere, B., Schraen-Maschke, S., et al.
  • NPC Niemann-Pick disease type C
  • MPS III B mucopolysaccharidosis III B
  • DM1 myotonic dystrophies
  • DM1 Sergeant, N., Sablonniere, B., Schraen-Maschke, S., et al.
  • tau pathology may also contribute more generally to cognitive deficits and decline, including in mild cognitive impairment (MCI) (see e.g. Braak, H., Del Tredici, K, Braak, E. (2003) Spectrum of pathology. In Mild cognitive impairment: Aging to Alzheimer's disease edited by Petersen, R.C.; pp. 149-189 ).
  • MCI mild cognitive impairment
  • tauopathies or “diseases of tau protein aggregation”.
  • the tauopathy is selected from the list consisting of the indications above, i.e., AD, Pick's disease, PSP, FTD, FTDP-17, DDPAC, PPND, Guam-ALS syndrome, PNLD, and CBD and AgD, DS, SSPE, DP, PEP, DLB and MCI.
  • the tauopathy is Alzheimer's disease (AD).
  • compositions of the invention may be used in the treatment or prophylaxis of TDP-43 proteinopathies e.g. frontotemporal lobe dementia associated with TDP-43 (FTLD-TDP43), amyotrophic lateral sclerosis (ALS) and overlapping syndromes, and semantic dementia and FTDP-17 ( Chen-Plotkin, AS, Lee, VMY, Trojanowski, JQ (2010) TAR DNA-binding protein 43 in neurodegenerative disease. Nature Reviews Neurology 6:211-220 ).
  • TDP-43 proteinopathies e.g. frontotemporal lobe dementia associated with TDP-43 (FTLD-TDP43), amyotrophic lateral sclerosis (ALS) and overlapping syndromes, and semantic dementia and FTDP-17 ( Chen-Plotkin, AS, Lee, VMY, Trojanowski, JQ (2010) TAR DNA-binding protein 43 in neurodegenerative disease. Nature Reviews Neurology 6:211-220 ).
  • one aspect of the present invention pertains to a solid dosage form composition, as described in the claims herein, for use in a method of treatment or prophylaxis (e.g. of a tauopathy condition or TDP-43 proteinopathy) of the human or animal body by therapy.
  • a method of treatment or prophylaxis e.g. of a tauopathy condition or TDP-43 proteinopathy
  • Also described herein is a method of treatment or prophylaxis of a disease of protein aggregation as described herein, which method comprises administering to a subject a solid dosage form composition such as to inhibit the aggregation of the protein (e.g. tau protein) associated with said disease state.
  • a solid dosage form composition such as to inhibit the aggregation of the protein (e.g. tau protein) associated with said disease state.
  • a solid dosage form composition of the invention for use in a method of treatment or prophylaxis of a disease of protein aggregation as described above, which method comprises administering to a subject the solid dosage form composition such as to inhibit the aggregation of the protein associated with said disease state.
  • a method of inhibiting production of protein aggregates e.g. in the form of paired helical filaments (PHFs), optionally in neurofibrillary tangles (NFTs)
  • PHFs paired helical filaments
  • NFTs neurofibrillary tangles
  • a drug product for the treatment of a disease state associated with protein aggregation in a mammal suffering therefrom comprising a container labeled or accompanied by a label indicating that the drug product is for the treatment of said disease, the container containing one or more dosage units each comprising a solid dosage form composition of the invention.
  • a first embodiment of the manufacturing process of the second aspect of this invention is simple direct compression.
  • the tablet ingredients i.e. MTC, diluent(s) and other optional excipients
  • MTC solid, particulate form
  • diluent(s) and other optional excipients are blended together in solid, particulate form to create an intimate mixture, e.g. in a tumbling blender, and then compressed using a tablet machine.
  • the composition is prepared by a dry granulation process.
  • Dry granulation refers to the process of granulating without the use of granulating fluids.
  • at least one of its constituents, either the active ingredient or a diluent must have cohesive properties. Dry granulation may be performed by a process known as "slugging". In “slugging”, the material to be granulated is first made into a large compressed mass or "slug”, typically using a tablet press with large flat-faced tooling (an example of a linear press is illustrated in US-4,880,373 ).
  • a fairly dense slug may be formed by allowing sufficient time for the air to escape from the material to be compacted. Compressed slugs are then milled through a desired mesh screen manually or automatically as, for example, by way of a comminuting mill. Formation of granules by "slugging” is also known as precompression. When tablets are made from the granulated slugged material, the process is referred to as the "double compression method".
  • Dry granulation may also be performed using a "roller compactor".
  • a roller compactor material particles are consolidated and densified by passing the material between two high-pressure rollers.
  • the densified material from a roller compactor is then reduced to a uniform granule size by milling.
  • the uniform granules may then be mixed with other substances, such as a lubricant, to tablet the material (as, for example, by way of a rotary tableting machine).
  • roller compaction is used in other industries, such as the food industry, animal feed industry and fertilizer industry.
  • Dry granulation is nowadays generally understood to mean roller compaction or slugging, and is well known to those skilled in the art (see, for instance, Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman, and Schwartz (Eds); Marcel Dekker, Inc, 2nd Edition, 1989 ) and Remington's Pharmaceutical Sciences (A. R. Gennaro (Ed); Mack Publishing Co, Easton, PA, 18th edition, 1990 )).
  • MTC tablets are prepared by moist granulation of the excipients and incorporation of the MTC extra-granularly.
  • a process involves wet massing diluents such as lactose and/or microcrystalline cellulose with water, optionally with the addition of a binder such as polyvinyl pyrrolidone.
  • the wet mass is passed through a mesh and dried to form granules.
  • the MTC and any remaining excipients, such as a lubricant, are then blended with the dry granules and compressed to form tablets.
  • capsules comprising MTC which has been formulated with diluents and other optionally other excipients as described herein.
  • Such capsules may be prepared from materials well known in the art e.g. Gelatin, Gelatin ⁇ PEG, HPMC and so on - see " Pharmaceutical Capsules; 2nd Revised Edition” Podczeck & Jones (Eds), Pharmaceutical Press 2004 .
  • X-ray powder diffractograms were obtained using a Bruker D8 Advance diffractometer with LynxEye detector. Measurements were performed in the Bragg-Brentano reflection geometry with Cu K ⁇ radiation ( ⁇ 1.54180 ⁇ at 40 kV/40mA. Data points were collected with 0.02 step size in 20 and 37s accumulation time per step. The samples were prepared on silicon single crystal sample holders with 1.0mm depth and 12mm diameter. All samples were rotated at 30 rpm during the measurement.
  • Figures 1A-1E show respectively the X-ray diffractograms of Forms A-E of MTC.
  • TG and TG-FTIR of hydrate form A consistently indicated a weight loss of 21.7%, which corresponds with good approximation to 5 molecules of water per molecule of MTC.
  • the separation between water loss and decomposition was much more distinct in TG than in TG-FTIR, which can be explained by the different measurement setup (open pan versus pan with micro hole).
  • a DSC measurement was performed with a sample of MTC pentahydrate in a closed gold pan with a scanning rate of 100 K/min (see Figure 2 ).
  • AH 116 J/g
  • a much smaller, broadened peak was observed between approximately 150°C and 180°C which can be attributed to the dissolution of the remaining solid in the liquid phase. Above 190°C there is evidence of decomposition (exothermic signals).
  • thermodynamic stability of MTC hydrates is defined for a given set of environmental conditions such as temperature (T) and relative humidity (RH).
  • Figure 3 shows the free energy of Forms A, B and C as a function of RH at a fixed T (25°C).
  • MTC Form B is not thermodynamically stable, though it is kinetically stable in a certain range of T and RH.
  • Form A is thermodynamically stable at high RH, and at relatively low T.
  • Form A may also exist as a metastable state in a broader range of T and RH.
  • Form B can transform into Form C (and probably even Form D). There is a risk that on prolonged storage and during processing such as film coating, transformation of Form B into Form C or D could also occur.
  • FIG 4 shows the stability domain of MTC Form A.
  • the shaded area represents all combinations of water activity (RH) and temperature at which Form A is thermodynamically stable.
  • the black dots represent experimental data points for the equilibrium T and RH values for the transformation between form A and form C.
  • the Figure shows that Form A is relatively unstable below 50% RH at 40°C and also below 40% RH at 25°C.
  • Tablets having the following compositions were prepared by a direct compression method: Tablet strength (mg MTC/tablet) 50mg 75mg 100mg 125mg Ingredient mg/tablet MTC (free base equivalent) 73.61 110.41 147.22 184.02 Microcrystalline cellulose (Avicel PH 102) 230.00 230.00 230.00 287.50 Spray-dried lactose 127.39 90.59 53.78 67.23 Crosslinked polyvinylpyrrolidone 15.00 15.00 15.00 18.75 magnesium stearate 4.00 4.00 4.00 5.00 TOTAL TABLET WEIGHT/mg 450 450 450 562.5
  • the MTC (Form A), microcrystalline cellulose, spray-dried lactose, cross-linked polyvinylpyrrolidone and magnesium stearate were blended in a tumbling blender, and then compressed using a tablet machine.
  • Similar formulations may be prepared by a dry granulation method.
  • the mix of microcrystalline cellulose, spray-dried lactose, cross-linked polyvinylpyrrolidone and magnesium stearate can be dry granulated using a roller compactor and then milled, e.g. with an oscillating granulator.
  • half of the magnesium stearate is used prior to roller compaction and half of the magnesium stearate may be added to the granulation and blended prior to compression on a conventional tablet machine.
  • the tablet cores may then be film coated with an aqueous suspension of Opadry blue (registered trademark of Colorcon for a series of film coating systems).
  • Tablets having the following compositions were prepared by a direct compression method: Tablet strength (mg MTC/tablet) 50mg 75mg 100mg 125mg Ingredient mg/tablet MTC (free base equivalent) 73.61 110.41 147.22 184.02 Spray-dried mannitol 357.39 320.59 283.78 354.73 Crosslinked polyvinylpyrrolidone 15.00 15.00 15.00 18.75 Magnesium stearate 4.00 4.00 4.00 5.00 TOTAL TABLET WEIGHT/mg 450 450 450 562.5
  • the MTC (Form A), microcrystalline cellulose, spray-dried mannitol, crosslinked polyvinylpyrrolidone and magnesium stearate were blended in a tumbling blender then compressed using a tablet machine.
  • Similar formulations may be prepared by a dry granulation method.
  • the mix of microcrystalline cellulose, spray-dried lactose, cross-linked polyvinylpyrrolidone and magnesium stearate can also be dry granulated using a roller compactor and then milled with an oscillating granulator using a 20 mesh screen.
  • half of magnesium stearate is used prior to roller compaction and half of the magnesium stearate may be added to the granules and blended prior to compression on a conventional tablet machine.
  • the tablet cores may then be film coated with an aqueous suspension of Opadry blue (registered trademark of Colorcon for a series of film coating systems).
  • Tablets having the following compositions were prepared by a direct compression method: Tablet strength (mg MTC/tablet) 50mg 50mg 50mg 75mg 75mg 75mg Food mg/tablet MTC (free base equivalent) 73.6 73.6 73.6 110.4 1 110.4 1 110.4 1 Microcrystalline cellulose (Avicel PH 102) 115 172.5 Spray-dried lactose 26.9 141.9 40.35 212.8 5 Spray-dried mannitol 141.9 212.8 5 Crosslinked polyvinylpyrrolidone 7.5 7.5 7.5 11.25 11.25 11.25 Magnesium Stearate 2 2 2 3.00 3.00 3.00 TOTAL TABLET WEIGHT/mg 225 225 225 337.5 337.5 337.5 337.5 337.5 337.5
  • the MTC (Form A) and excipients were blended in a tumbling blender, and then compressed using a tablet machine.
  • Similar formulations may be prepared by a dry granulation method.
  • the mix of excipients may alternatively be dry granulated using a roller compactor and then milled with an oscillating granulator using a 20 mesh screen.
  • half of magnesium stearate may be used prior to roller compaction and half of the magnesium stearate is added to the granues and blended prior to compression on a conventional tablet machine.
  • the tablet cores may then be film coated with an aqueous suspension of Opadry blue (registered trademark of Colorcon for a series of film coating systems).
  • Tablets having the following compositions were prepared by a direct compression method: Tablet strength (mg MTC/tablet) 25 50 75 100 Ingredient mg/tablet MTC (free base equivalent) 36.80 73.60 110.43 147.24 Microcrystalline cellulose (Avicel PH 102) 230 230 230 230.00 Spray-dried Lactose 149.20 112.40 75.57 38.76 Croscarmellose sodium 30.00 30.00 30.00 30.00 Magnesium stearate 4.00 4.00 4.00 4.00 TOTAL TABLET WEIGHT/mg 450 450 450 450 450 450
  • Tablet strength (mg) Hardness range (kg) Thickness range (mm) Mean weight of 20 tablets (mg) Table weight range of 20 tablets (mg) Disintegration time (min) 25 13.4-16.4 4.8-4.9 451 447-455 2 50 14.31-18.60 4.8 451.77 446-455 1.5 75 19.5-22.0 4.7-4.9 451.5 445-458 1.5 100 19.2-23.8 4.8-5.1 451 446-457 1.5
  • MTC 30 mg tablets prepared by direct compression with microcrystalline cellulose (155mg/tablet), spray dried lactose (50mg) and sodium starch glycolate; 250mg round:
  • the blended material was compressed to a tablet weight of 250mg at three different pressures.
  • Properties of the resulting tablets were: Pressure 1 Pressure 2 Pressure 3 Weight, mean 249mg 250mg 251mg Hardness, mean 10.8kg 14.5kg 15.3kg Thickness, mean 4.5mm 4.3mm 4.3mm Disintegration time, mean 50 seconds 2.40 minutes 1 minute Friability 2% 0.39% 1.3%
  • MTC 30mg tablets prepared by direct compression with microcrystalline cellulose and croscarmellose sodium; tablet weight 250mg
  • the blended material was compressed to a tablet weight of 250mg.
  • Properties of the resulting tablets were: Parameter Result Description Blue round tablet Thickness range mm 4.3 - 4.4 Hardness range 5.0 - 10.5kg Weight range for 20 tablets 212 - 270mg Mean weight of 20 tablets 247.51mg Friability 0.26% Disintegration time 1 to 5 minutes
  • MTC 30 mg tablets prepared by direct compression with microcrystalline cellulose, spray dried lactose and croscarmellose sodium; tablet weight 250mg:
  • the blended material was compressed to a tablet weight of 250mg.
  • Properties of the resulting tablets were: Parameter Results Description Blue round tablets Thickness, mean 4.8mm Hardness, mean 7.5kg Hardness range for 20 tablets 6.0 to 8.8kg Weight of 20 tablets, mean 248.4mg Friability 0.31% Disintegration time, mean About 1minute
  • the blended material was compressed to a tablet weight of 210mg.
  • Properties of the resulting tablets were: Parameter Result Weight 202.5mg Hardness. mean 7.9kg Thickness, mean 4.2mm Disintegration time, mean 36 seconds Friability 0.13%
  • the disintegrant used can be replaced by crospovidone without affecting compressibility, disintegration and dissolution properties.
  • the blended material was compressed to a weight of 420mg (Oblong tablets).
  • Properties of the resulting tablets were: Parameter Result Weight, mean 420.1mg Hardness mean 12.9Kg Thickness mean 5.2mm Disintegration time mean 50 seconds Friability 0.1%
  • the resulting tablets had the following properties: Parameter Result Description Blue round tablets Thickness range 4.5 - 4.6mm Hardness range 7.1 - 10.1kg Weight of 20 tablets, mean 252.03mg Friability 0.22% Disintegration time 2.0 - 2.5 minutes
  • the resulting tablets had the following properties: Parameters Results Description Blue round tablets Thickness 4.5 - 4.6mm Hardness 12.0 - 16.4kg Tablet weight range (20 tablets) 245-254mg Friability loss Less than 0.1%
  • Ingredient Tablet strength (mg MTC/tablet) 30mg 60mg MTC (expressed as trihydrate) 30mg 60mg Microcrystalline cellulose, Avicel PH 102 92.5mg 77.5mg Lactose monohydrate 60mg 45mg Povidone (Plasdone K30) 2.5mg 2.5mg Croscarmellose sodium 22.5 22.5mg Magnesium stearate 2.5mg 2.5mg
  • bioavailability The rate and extent to which the active ingredient is absorbed from a pharmaceutical dosage form and becomes available at the site of action is defined as bioavailability ( Chen, M. L. et al. Bioavailability and bioequivalence: an FDA regulatory overview, Pharm. Res. 2001, 18, 1645-1648 ).
  • bioavailability is assessed based on drug concentrations in the general circulation.
  • the systemic exposure is determined by measuring the blood or plasma concentrations of the active drug at numerous time points following the drug administration and calculation of the area under the concentration-time curve (AUC). Blood/plasma drug concentration time profiles are affected by the dynamics of dissolution, solubility, absorption, metabolism, distribution, and elimination.
  • Absorption from a solid oral dosage form after administration can depend on the dissolution of the solid oral dosage form, which results from a series of simultaneous and successive processes, and the permeability across the gut wall of the gastrointestinal tract.
  • in vitro dissolution may be relevant to the prediction of in vivo plasma concentrations and therefore bioavailability (Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 1997).
  • in vitro dissolution tests for immediate release solid oral dosage forms are used to assess the quality of a drug product.
  • An immediate release product allows the ingredient or active moiety to dissolve in the gastrointestinal tract, without causing any delay or prolongation of the dissolution or absorption of the drug.
  • Requirements for dissolution testing of immediate release products are set out in the Guidance for Industry (CDER 1997) "Dissolution testing for immediate release solid oral dosage forms ", ( CDER 1997) “Immediate release solid oral dosage forms - Scale up and Postapproval Changes", ICH Guidance Q6A , Specifications: Test Procedures and Acceptance Criteria For New Drug Substances And New Drug Products.
  • compositions according to the invention can be dissolution tested in a USP-2 apparatus in 900ml of 0.1N HCl, with paddles rotating at 50-75 rpm.
  • Compositions according to the invention exhibit at least the acceptance criteria cited for Stage 1 (S1) testing in the USP 32 (The United States Pharmacopeia, edited by the United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852; Published by Rand McNally, Inc., 32nd Edition, 2008 ):
  • the coating pan was warmed without the tablets for 10-15 minutes with an inlet air temperature between 45°C and 75° C, preferably 50 - 65° C, until the exhaust temperature reaches 35-55°C, preferably 40-50°C.
  • the MTC tablets were sprayed with the aqueous film coat at a spray rate such that the bed temperature is maintained at 38-48°C, preferably 42-44°C. Once the required weight gain was achieved, spraying was stopped and the temperature inlet control was switched off. The tablets were allowed to cool on a jog cycle until bed temperature reached room temperature.
  • a similar method may be used for non-aqueous film coating.
  • the coating pan was warmed with the tablets for 10 minutes with an inlet air temperature around 50°C, preferably around 40°C, until the bed temperature reached 30-45°C, preferably 35-40°C.
  • the MTC tablets were sprayed with the aqueous film coat at a starting spray rate such that the bed temperature was maintained at 28-44°C, preferably 30-35°C.
  • the inlet temperature was increased to around 50°C, preferably 45°C, the spray rate was used to keep the bed temperature at 28-44°C, preferably 35-40°C.
  • the inlet temperature was increased to around 60°C, preferably 50°C, and the spray rate increased to keep the bed temperature at 28-44°C, preferably 35-40°C.
  • spraying was stopped and the temperature inlet control was switched off. The tablets were allowed to cool on a jog cycle until the bed temperature reached room temperature.
  • a similar method may be used for non-aqueous film coating.
  • An example of a tablet formulation that may be film-coated by one of the above methods is: Ingredient mg/tablet MTC 147.24 MCC 230.00 Spray-dried lactose 38.76 Crosscarmelose sodium 30.00 Magnesium stearate 4.00 Tablet weight 450.00
  • MTC tablets were manufactured at various tablet strengths, stored under controlled conditions of temperature and relative humidity, and the polymorphic forms analysed by XRPD: MTC Form A tablets; stored in aluminium blisters Tablet strength Storage conditions Storage time / months Polymorphic form 50mg 25°C / 65% RH 10.5 A 25mg 25°C / 65% RH 9 A 25mg 40°C / 75% RH 6 A
  • MTC capsules for example in Gelatin or HPMC, may be prepared using compositions of MTC with diluents, disintegrants and lubricants which may be qualitatively similar to those discussed above in respect of the tablet formulations.
  • An example capsule composition containing 25, 50, 75, 100 mg of MTC as free base equivalent in Gelatin or HPMC capsule shells is as follows: Capsule strength in (mg of MTC) 25 50 75 100 Ingredient Function mg/capsule MTC (free base equivalent) Drug 36.80 73.61 110.41 147.22 Spray-dried mannitol Diluent 238.70 201.89 165.09 128.28 Cross-linked polyvinylpyrrolidone Disintegrant 3.00 3.00 3.00 3.00 Magnesium stearate Lubricant 1.50 1.50 1.50 1.50 Total 280.00 280.00 280.00 280.00 280.00 280.00 280.00 280.00 280.00

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (18)

  1. Pharmazeutische Zusammensetzung in fester Dosierungsform, die eine Tablette ist, die als Wirkstoff Methylthioniumchlorid (MTC) umfasst, wobei die Zusammensetzung weiters zumindest einen für Direktpressung geeigneten Verdünner umfasst, der mikrokristalline Cellulose oder ein Zucker ist,
    wobei das MTC in einer im Wesentlichen reinen und stabilen polymorphen Form vorliegt, die die polymorphe Form A ist,
    wobei die Menge an MTC in der Zusammensetzung mehr als 10 Gew.-% beträgt und
    wobei die Zusammensetzung durch ein Verfahren erhalten wird, das die Trockenpressung eines innigen Pulvergemischs des MTC in einer im Wesentlichen reinen polymorphen Form mit dem zumindest einen für Direktkompression geeigneten Verdünner und gegebenenfalls einem oder mehreren weiteren Exzipienten umfasst.
  2. Zusammensetzung nach Anspruch 1, wobei das Verfahren ein Direktpressverfahren ist, in dem MTC, ein oder mehrere Verdünner und weitere optionale Exzipienten in Form fester Teilchen vermischt werden, um ein inniges Gemisch zu bilden, und anschließend unter Verwendung einer Tablettiermaschine verpresst werden.
  3. Zusammensetzung nach Anspruch 1, wobei das Verfahren ein Trockengranulationsverfahren ist, in dem MTC, ein oder mehrere Verdünner und weitere optionale Exzipienten zu einer gepressten Masse geformt, gemahlen und anschließend unter Verwendung einer Tablettiermaschine verpresst werden.
  4. Zusammensetzung nach Anspruch 1, wobei das Verfahren ein Nassgranulationsverfahren ist, in dem der/die Verdünner unter Verwendung eines Granulationsmediums nass geknetet wird/werden und die nasse Masse anschließend getrocknet wird, um ein Granulat zu bilden, das daraufhin mit MTC vermischt und zu Tabletten verpresst wird.
  5. Zusammensetzung nach einem der vorangegangenen Ansprüche, wobei:
    (i) die Menge an MTC in der Zusammensetzung mehr als 20 Gew.-% oder mehr als 30 Gew.-% und gegebenenfalls weniger als 75 Gew.-% oder weniger als 60 Gew.-% oder weniger als 50 Gew.-% beträgt, beispielsweise zwischen 10 Gew.-% (oder 20 Gew.-% oder 30 Gew.-%) und 70 Gew.-% (oder 60 Gew.-% oder 50 Gew.-%); und/oder
    (ii) die Zusammensetzung zumindest 15 Gew.-%, zumindest 20 Gew.-%, zumindest 30 Gew.-%, zumindest 40 Gew.-% oder zumindest 50 Gew.-% an Verdünner(n) umfasst.
  6. Zusammensetzung nach einem der vorangegangenen Ansprüche, wobei der/ die Verdünner aus der aus mikrokristalliner Cellulose, Lactose und Mannit bestehenden Gruppe ausgewählt ist/sind.
  7. Zusammensetzung nach einem der vorangegangenen Ansprüche, die weiters ein Schmiermittel, gegebenenfalls 0,5 bis 2,0 Gew.-% Schmiermittel, umfasst,
    wobei das Schmiermittel gegebenenfalls aus der aus Magnesiumstearat, Calciumstearat und Stearinsäure bestehenden Gruppe ausgewählt ist.
  8. Zusammensetzung nach einem der vorangegangenen Ansprüche, die weiters Folgendes umfasst:
    (i) einen oder mehrere Zerfallsbeschleuniger, der/die aus der aus vernetztem Polyvinylpyrrolidon, Natriumstärkeglykolat, vernetzter Natriumcarboxymethylcellulose (Natriumcroscarmellose) und vorgelatinierter Stärke bestehenden Gruppe ausgewählt ist/sind; und/oder
    (ii) ein Bindemittel, das aus der aus Cellulosederivaten (Carboxymethylcellulose, Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxyethylcellulose, Ethylcellulose, mikrokristalliner Cellulose) und Zuckern wie z.B. Lactose, Saccharose, Dextrose, Glucose, Maltodextrin und Mannit, Xylit, Polymethacrylaten, Polyvinylpyrrolidon, Sorbit, vorgelatinierter Stärke, Alginsäuren und Salzen davon wie z.B. Natriumalginat, Magnesiumaluminiumsilikat, Polyethylenglykol bestehenden Gruppe ausgewählt ist.
  9. Zusammensetzung nach einem der vorangegangenen Ansprüche, wobei eine Filmbeschichtung aufgetragen wurde, wobei die Filmbeschichtung gegebenenfalls Hydroxypropylmethylcellulose (HPMC) oder partiell hydrolysierten Polyvinylalkohol (PVA) umfasst.
  10. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung nach Anspruch 1, wobei das Verfahren die Trockenpressung eines innigen Pulvergemischs von Methylthioniumchlorid (MTC) in einer im Wesentlichen reinen polymorphen Form, die die polymorphe Form A ist, mit zumindest einem für Direktpressung geeigneten Verdünner und gegebenenfalls einem oder mehreren weiteren Exzipienten umfasst.
  11. Verfahren nach Anspruch 10, wobei das Verfahren die Direktpressung eines innigen Pulvergemischs von MTC in einer im Wesentlichen reinen polymorphen Form mit zumindest einem für Direktpressung geeigneten Verdünner und gegebenenfalls einem oder mehreren weiteren Exzipienten umfasst.
  12. Verfahren nach Anspruch 10, das ein Direktpressverfahren ist, in dem MTC, ein oder mehrere Verdünner und weitere optionale Exzipienten in Form fester Teilchen vermischt werden, um ein inniges Gemisch zu erzeugen, und anschließend unter Verwendung einer Tablettiermaschine verpresst werden.
  13. Verfahren nach Anspruch 10, das ein Trockengranulationsverfahren ist, in dem MTC, ein oder mehrere Verdünner und weitere optionale Exzipienten zu einer gepressten Masse geformt, gemahlen und anschließend unter Verwendung einer Tablettiermaschine verpresst werden.
  14. Verfahren nach Anspruch 10, das ein Feuchtgranulationsverfahren ist, in dem der/die Verdünner unter Verwendung eines Granulationsmediums nass geknetet wird/werden und die nasse Masse anschließend getrocknet wird, um ein Granulat zu bilden, das daraufhin mit MTC vermischt und zu Tabletten verpresst wird.
  15. Verfahren nach einem der Ansprüche 10 bis 14, das weiters den Schritt des Auftragens einer Filmbeschichtung auf die Tabletten umfasst,
    wobei der Schritt des Auftragens einer Filmbeschichtung in einer Beschichtungstrommel durchgeführt wird und das Vorwärmen der Beschichtungstrommel vor dem Zuführen der zu beschichtenden Tabletten umfasst,
    wobei gegebenenfalls die Temperatur der Tabletten während der Beschichtung bei einer Temperatur von 38-48 °C, noch bevorzugter 42-44 °C gehalten wird.
  16. Zusammensetzung in fester Dosierungsform nach einem der Ansprüche 1 bis 9 zur Verwendung in einem Verfahren zur Behandlung oder Prophylaxe eines Krankheitszustands in einem Patienten, wobei das Verfahren das Verabreichen einer therapeutisch wirksamen Menge der Zusammensetzung an den Patienten umfasst.
  17. Zusammensetzung zur Verwendung nach Anspruch 16, wobei die Krankheit eine Tauopathie ist.
  18. Im Wesentlichen feuchtigkeitsundurchlässige Blisterpackung, die eine Zusammensetzung nach einem der Ansprüche 1 bis 9 umfasst.
EP11802119.5A 2010-11-30 2011-11-30 Formulierungen enthaltend methylthioninium chlorid Active EP2645994B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41816410P 2010-11-30 2010-11-30
PCT/GB2011/001662 WO2012072977A2 (en) 2010-11-30 2011-11-30 Compound formulations

Publications (2)

Publication Number Publication Date
EP2645994A2 EP2645994A2 (de) 2013-10-09
EP2645994B1 true EP2645994B1 (de) 2017-11-01

Family

ID=45418703

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11802119.5A Active EP2645994B1 (de) 2010-11-30 2011-11-30 Formulierungen enthaltend methylthioninium chlorid

Country Status (10)

Country Link
US (1) US9192611B2 (de)
EP (1) EP2645994B1 (de)
JP (1) JP6093707B2 (de)
CN (1) CN103379901B (de)
AU (1) AU2011334679B2 (de)
CA (1) CA2818068C (de)
ES (1) ES2655492T3 (de)
MY (1) MY163074A (de)
SG (2) SG190406A1 (de)
WO (1) WO2012072977A2 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021116611A1 (fr) * 2019-12-12 2021-06-17 Universite de Bordeaux Formulation pour le bleu de methylene et procede

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014153444A (ja) * 2013-02-06 2014-08-25 Konica Minolta Inc 位相差フィルム、偏光板及び液晶表示装置
MX2019000946A (es) 2016-07-25 2019-05-13 Wista Lab Ltd Administracion y dosificacion de diaminofenotiazinas.
WO2023232764A1 (en) 2022-05-31 2023-12-07 Wista Laboratories Ltd. Treatment of neurodegenerative disorders utilising methylthioninium (mt)-containing compounds
WO2024063700A1 (en) 2022-09-21 2024-03-28 Yin Sze Loh Oral formulation of diaminophenothiazines and methods of making and using the same in the treatment and/or prevention of diseases

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4880373A (en) 1988-04-28 1989-11-14 The Upjohn Company Tablet press
JPH0840942A (ja) * 1994-07-29 1996-02-13 Kanegafuchi Chem Ind Co Ltd 薬物放出制御製剤
GB9506197D0 (en) 1995-03-27 1995-05-17 Hoffmann La Roche Inhibition of tau-tau association.
GB0101049D0 (en) 2001-01-15 2001-02-28 Univ Aberdeen Materials and methods relating to protein aggregation in neurodegenerative disease
GB0106953D0 (en) 2001-03-20 2001-05-09 Univ Aberdeen Neufofibrillary labels
GB0322756D0 (en) 2003-09-29 2003-10-29 Univ Aberdeen Methods of chemical synthesis
EP2322517B1 (de) 2004-09-23 2019-04-24 WisTa Laboratories Ltd. Verfahren zur chemischen synthese und aufreinigung von diaminophenothiaziniumverbindungen einschliesslich methylthioniniumchlorid (mtc)
US7790881B2 (en) * 2004-09-23 2010-09-07 Wista Laboratories Ltd. Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (MTC)
DE602005011326D1 (de) * 2004-10-19 2009-01-08 Krka Tovarna Zdravil D D Feste pharmazeutische zusammensetzung mit donepezilhydrochlorid
CN101304731B (zh) * 2005-08-24 2012-06-20 惠氏公司 醋酸苯卓昔芬制剂及其生产方法
DK1808165T3 (da) * 2006-01-05 2009-08-03 Teva Pharma Törre formuleringer af aripiprazol
PT2013191E (pt) 2006-03-29 2010-10-29 Wista Lab Ltd Sais de 3,7-diamino-10h-fenotiazina e a sua utilização
US20080317678A1 (en) * 2007-06-22 2008-12-25 Szymczak Christopher E Laser Marked Dosage Forms
ES2546819T3 (es) 2007-10-03 2015-09-28 Wista Laboratories Ltd. Uso terapéutico de las diaminofenotiazinas
EP2227766A2 (de) 2007-11-05 2010-09-15 Wista Laboratories Ltd. Systeme für klinische versuche
MY161463A (en) * 2009-09-24 2017-04-14 Wista Lab Ltd Process for the preparation of substantially pure methylthionium chloride pentahydrate form a

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021116611A1 (fr) * 2019-12-12 2021-06-17 Universite de Bordeaux Formulation pour le bleu de methylene et procede
FR3104438A1 (fr) * 2019-12-12 2021-06-18 Universite de Bordeaux Formulation pour le bleu de methylene et procede

Also Published As

Publication number Publication date
EP2645994A2 (de) 2013-10-09
CA2818068C (en) 2019-06-11
ES2655492T3 (es) 2018-02-20
JP6093707B2 (ja) 2017-03-08
US9192611B2 (en) 2015-11-24
AU2011334679A1 (en) 2013-07-18
MY163074A (en) 2017-08-15
US20130243858A1 (en) 2013-09-19
AU2011334679B2 (en) 2016-12-15
CN103379901B (zh) 2018-04-03
JP2013544272A (ja) 2013-12-12
CA2818068A1 (en) 2012-06-07
WO2012072977A2 (en) 2012-06-07
CN103379901A (zh) 2013-10-30
WO2012072977A8 (en) 2012-09-20
SG10201602111VA (en) 2016-04-28
SG190406A1 (en) 2013-06-28
WO2012072977A3 (en) 2012-08-16

Similar Documents

Publication Publication Date Title
TWI778983B (zh) 包含2-羥基-6-((2-(1-異丙基-1h-吡唑-5-基)吡啶-3-基)甲氧基)-苯甲醛之片劑
EP3024442B1 (de) Zusammensetzungen mit amorphem dapagliflozin
EP2974720B1 (de) Präparat mit verzögerter mosaprid-freisetzung zur erreichung pharmakologischer klinischer wirkungen zur täglichen verabreichung
EP2645994B1 (de) Formulierungen enthaltend methylthioninium chlorid
MX2009002336A (es) Composiciones de imatinib.
JP2008536922A (ja) オランザピンの医薬用経口崩壊錠
JP6215940B2 (ja) ８−［（３ｒ）−３−アミノ−１−ピペリジニル］−７−（２−ブチン−１−イル）−３，７−ジヒドロ−３−メチル−１−［（４−メチル−２−キナゾリニル）メチル］−１ｈ−プリン−２，６−ジオンまたはその医薬的に許容され得る塩を含む安定な医薬組成物
AU2019232937B2 (en) Ceritinib formulation
CN106822112B (zh) 一种替米沙坦氨氯地平双层片的制备方法
CN106511291A (zh) 一种盐酸阿考替胺缓释片剂及其制备方法
Buwade et al. Advantages of immediate release tablets over the other tablet forms
WO2020111089A1 (ja) 医薬組成物
US9949964B2 (en) Tesofensine compositions
JP2012180280A (ja) 貯蔵安定性が改善された固形製剤
BRPI0621739A2 (pt) formulação estável que consiste em drogas sensìveis à umectação e seu procedimento de fabricação
EP4183390A1 (de) Pharmazeutische schmelztablettendosierungsform von edoxaban
JP2009536643A (ja) ２−ｎ−｛５−［［４−［２−（メチル−２−ピリジニルアミノ）エトキシ］フェニル］メチル］−２，４−チアゾリジンジオン｝−ブタン二酸、製造方法、および、ロシグリタゾンマレアートとの組成物
Bhaskar et al. A review on formulation approaches in immediate release tablet
CN107648237B (zh) 氨基嘧啶类化合物的药物组合物及其制备方法
CN118356426A (zh) 一种包含并环化合物的药物组合物及其制备方法和应用
WO2019170795A1 (en) A pharmaceutical solid oral dosage form of solifenacin
JP2021104939A (ja) ラメルテオンを含む錠剤および医薬組成物
BR112019020269A2 (pt) formulação farmacêutica

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20130620

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: WISTA LABORATORIES LTD.

RIN1 Information on inventor provided before grant (corrected)

Inventor name: KHAN, KARRAR, AHMAD

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1184386

Country of ref document: HK

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20140623

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: WISTA LABORATORIES LTD.

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/48 20060101ALI20170419BHEP

Ipc: A61K 9/20 20060101ALI20170419BHEP

Ipc: C07D 279/18 20060101ALI20170419BHEP

Ipc: A61K 9/14 20060101AFI20170419BHEP

Ipc: A61K 9/16 20060101ALI20170419BHEP

Ipc: A61P 25/28 20060101ALI20170419BHEP

Ipc: A61K 31/5415 20060101ALI20170419BHEP

INTG Intention to grant announced

Effective date: 20170515

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: AT

Ref legal event code: REF

Ref document number: 941305

Country of ref document: AT

Kind code of ref document: T

Effective date: 20171115

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602011042984

Country of ref document: DE

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2655492

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20180220

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 941305

Country of ref document: AT

Kind code of ref document: T

Effective date: 20171101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180201

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180201

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180301

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180202

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602011042984

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171130

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1184386

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171130

26N No opposition filed

Effective date: 20180802

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20111130

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20171101

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230427

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20231023

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20231120

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20231201

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20231121

Year of fee payment: 13

Ref country code: IE

Payment date: 20231023

Year of fee payment: 13

Ref country code: FR

Payment date: 20231027

Year of fee payment: 13

Ref country code: DE

Payment date: 20231031

Year of fee payment: 13

Ref country code: CH

Payment date: 20231201

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20231031

Year of fee payment: 13